Identification of a de novo
            FOXP1
            mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2017.07.015 ◽

2017 ◽

Vol 60 (10) ◽

pp. 548-552 ◽

Cited By ~ 3

Author(s):

A.M. Matthews ◽

M. Tarailo-Graovac ◽

E.M. Price ◽

I. Blydt-Hansen ◽

A. Ghani ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

De Novo ◽

Copy Number Variant ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Spastic Paraplegia ◽

Chromosomal Copy Number ◽

Chromosomal Copy

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Increased burden of deleterious variants in essential genes in autism spectrum disorder

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613195113 ◽

2016 ◽

Vol 113 (52) ◽

pp. 15054-15059 ◽

Cited By ~ 30

Author(s):

Xiao Ji ◽

Rachel L. Kember ◽

Christopher D. Brown ◽

Maja Bućan

Keyword(s):

Autism Spectrum Disorder ◽

Large Scale ◽

De Novo ◽

Autism Spectrum ◽

Essential Genes ◽

Spectrum Disorder ◽

Model Organisms ◽

Disease Genes ◽

Priority List ◽

Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

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De novo Mutations (DNMs) in Autism Spectrum Disorder (ASD): Pathway and Network Analysis

Frontiers in Genetics ◽

10.3389/fgene.2018.00406 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 8

Author(s):

Aitana Alonso-Gonzalez ◽

Cristina Rodriguez-Fontenla ◽

Angel Carracedo

Keyword(s):

Autism Spectrum Disorder ◽

Network Analysis ◽

De Novo ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutations

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Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder

Translational Psychiatry ◽

10.1038/s41398-020-01107-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Hidekazu Kato ◽

Itaru Kushima ◽

Daisuke Mori ◽

Akira Yoshimi ◽

Branko Aleksic ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Histone Methylation ◽

Genetic Variants ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Gene Encoding ◽

Rare Genetic Variants ◽

Lysine Demethylase ◽

Methylation Patterns ◽

Sample Set

AbstractDysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

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Genomics of autism spectrum disorder: approach to therapy

F1000Research ◽

10.12688/f1000research.13865.1 ◽

2018 ◽

Vol 7 ◽

pp. 627 ◽

Cited By ~ 5

Author(s):

Fatma Ayhan ◽

Genevieve Konopka

Keyword(s):

Autism Spectrum Disorder ◽

Genetic Variants ◽

Molecular Mechanisms ◽

Three Dimensional ◽

Protein Translation ◽

Autism Spectrum ◽

Current Treatment ◽

Spectrum Disorder ◽

Current State ◽

Genetics And Genomics

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition with no current treatment available. Although advances in genetics and genomics have identified hundreds of genes associated with ASD, very little is known about the pathophysiology of ASD and the functional contribution of specific genes to ASD phenotypes. Improved understanding of the biological function of ASD-associated genes and how this heterogeneous group of genetic variants leads to the disease is needed in order to develop therapeutic strategies. Here, we review the current state of ASD research related to gene discovery and examples of emerging molecular mechanisms (protein translation and alternative splicing). In addition, we discuss how patient-derived three-dimensional brain organoids might provide an opportunity to model specific genetic variants in order to define molecular and cellular defects that could be amenable for developing and screening personalized therapies related to ASD.

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